The long-term objective of this research is to develop effective treatment approaches for memory impairments associated with excess glucocorticoid (GC) exposure. GCs are known to regulate brain metabolism, physiology and gene expression, particularly in the hippocampus, as well as memory function. Increased GC exposure including several days of exposure to the endogenous human GC, cortisol, at levels associated with major stress, is known to decrease memory performance. It is not known whether cortisol levels associated with mild to moderate stress can produce similar effects. In addition, indirect evidence from aging humans suggests that age-related increases in cortisol levels are associated with progressive age-related memory declines. This application proposes to identify the full range of plasma cortisol levels associated with adverse effects on human: memory, and to directly test the effect of cortisol on memory in older humans to define suspected age-related changes in GC effects. Evidence indicating age-related declines in hippocampal GC receptor function suggests that age-related memory decreases may not be a direct effect of increasing GC levels. Pilot data for application indicate age-related decreases in GC effects on memory. Confirmation of increased or decreased effects on memory in older humans is highly relevant to hypotheses that drive ongoing research to prevent related memory loss. This project aims to 1) define age-related changes in the effect of cortisol on memory, 2) define the relationship of plasma cortisol levels to memory across the full range of levels relevant to stress. Secondary aims include identification of additional variables that may modify vulnerability to cortisol-induced impairments. A double-blind, randomized, placebo-controlled, multiple fixed-dose comparison of oral cortisol treatment in younger and older adults will be used to measure cognitive and plasma variables at baseline, during treatment, and after washout. Doses are selected to produce a wide and continuous range of plasma cortisol levels associated with stress. Regression models and ANOVA will be used to assess the relationship of plasma cortisol levels and dose to memory, as well as relevant age effects. The results of this study are directly relevant to iatrogenic GC exposure, and to the effect of common physical and psychological stresses on memory function in all healthy humans. The results will address public health concerns about stress and learning, quantify of GC effects on memory during aging, and provide data on plasma cortisol levels relevant to treatment considerations (e.g., GC receptor antagonists, calcium channel blockers) for preventing this adverse effect on memory.